Chiara Pirillo

All Publications

• Lung influenza virus specific memory CD4 T cell location and optimal cytokine production are dependent on interactions with lung antigen-presenting cells. Mucosal immunology Hargrave, K. E., Worrell, J. C., Pirillo, C., Brennan, E., Masdefiol Garriga, A., I Gray, J., Purnell, T., Roberts, E. W., Kl MacLeod, M. 2024

  Abstract

  Influenza A virus (IAV) infection leads to the formation of mucosal memory CD4 T cells that can protect the host. An in-depth understanding of the signals that shape memory cell development is required for more effective vaccine design. We have examined the formation of memory CD4 T cells in the lung following IAV infection of mice, characterising changes to the lung landscape and immune cell composition. IAV-specific CD4 T cells were found throughout the lung at both primary and memory time points. These cells were found near lung airways and in close contact with a range of immune cells including macrophages, dendritic cells, and B cells. Interactions between lung IAV-specific CD4 T cells and MHCII+ cells during the primary immune response were important in shaping the subsequent memory pool. Treatment with an anti-MHCII blocking antibody increased the proportion of memory CD4 T cells found at lung airways but reduced interferon-gamma expression by IAV-specific immunodominant memory CD4 T cells. The immunodominant CD4 T cells expressed higher levels of PD1 than other IAV-specific CD4 T cells and PD1+ memory CD4 T cells were located further away from MHCII+ cells than their PD1-low counterparts. This distinction in location was lost in mice treated with anti-MHCII antibody. These data suggest that sustained antigen presentation in the lung impacts on the formation of memory CD4 T cells by regulating their cytokine production and location.

  View details for DOI 10.1016/j.mucimm.2024.06.001

  View details for PubMedID 38851589

• Cotransfer of antigen and contextual information harmonizes peripheral and lymph node conventional dendritic cell activation. Science immunology Pirillo, C., Al Khalidi, S., Sims, A., Devlin, R., Zhao, H., Pinto, R., Jasim, S., Shearer, P. A., Shergold, A. L., Donnelly, H., Bravo-Blas, A., Loney, C., Perona-Wright, G., Hutchinson, E., Roberts, E. W. 2023; 8 (85): eadg8249

  Abstract

  T cell responses against infections and cancer are directed by conventional dendritic cells (cDCs) in lymph nodes distant from the site of challenge. Migratory cDCs, which travel from the tissue to the lymph node, not only drive initial T cell activation but also transfer antigen to lymph node-resident cDCs. These resident cells have essential roles defining the character of the resulting T cell response; however, it is unknown how they can appropriately process and present antigens to suitably direct responses given their spatial separation. Here, using a novel strain of influenza A and a modified melanoma model, we show that tissue and lymph node cDC activation is harmonized and that this is driven by cotransfer of contextual cues. In the tumor, incomplete cDC activation in the tumor microenvironment is mirrored by lymph node-resident cDCs, whereas during influenza infection, pathogen-associated molecular patterns cotransferred with antigen drive TLR signaling in resident cDCs and their subsequent robust activation. This cotransfer mechanism explains how individual antigens can be handled distinctly by resident cDCs and how signals driving poor tumoral cDC activation further impact the lymph node. Our findings clarify how tissue context dictates antigenic and, consequently, T cell fate in the lymph node.

  View details for DOI 10.1126/sciimmunol.adg8249

  View details for PubMedID 37478193

  View details for PubMedCentralID PMC7616026

• Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness. Blood advances Pirillo, C., Birch, F., Tissot, F. S., Anton, S. G., Haltalli, M., Tini, V., Kong, I., Piot, C., Partridge, B., Pospori, C., Keeshan, K., Santamaria, S., Hawkins, E., Falini, B., Marra, A., Duarte, D., Lee, C. F., Roberts, E., Lo Celso, C. 2022; 6 (10): 3126-3141

  Abstract

  Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. Its prognosis remains poor, highlighting the need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias linked to loss of healthy hematopoietic stem and progenitor cells (HSPCs). The mechanisms behind HSPC decline are complex and still poorly understood. Here, intravital microscopy (IVM) of a well-established experimental model of AML allows direct observation of the interactions between healthy and malignant cells in the bone marrow (BM), suggesting that physical dislodgment of healthy cells by AML through damaged vasculature may play an important role. Multiple matrix metalloproteinases (MMPs), known to remodel extracellular matrix, are expressed by AML cells and the BM microenvironment. We reason MMPs could be involved in cell displacement and vascular leakiness; therefore, we evaluate the therapeutic potential of MMP pharmacological inhibition using the broad-spectrum inhibitor prinomastat. IVM analyses of prinomastat-treated mice reveal reduced vascular permeability and healthy cell clusters in circulation and lower AML infiltration, proliferation, and cell migration. Furthermore, treated mice have increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Analysis of a human AML transcriptomic database reveals widespread MMP deregulation, and human AML cells show susceptibility to MMP inhibition. Overall, our results suggest that MMP inhibition could be a promising complementary therapy to reduce AML growth and limit HSPC loss and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.

  View details for DOI 10.1182/bloodadvances.2021004321

  View details for PubMedID 35157757

  View details for PubMedCentralID PMC9131921

• Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML. Cell stem cell Duarte, D., Hawkins, E. D., Akinduro, O., Ang, H., De Filippo, K., Kong, I. Y., Haltalli, M., Ruivo, N., Straszkowski, L., Vervoort, S. J., McLean, C., Weber, T. S., Khorshed, R., Pirillo, C., Wei, A., Ramasamy, S. K., Kusumbe, A. P., Duffy, K., Adams, R. H., Purton, L. E., Carlin, L. M., Lo Celso, C. 2018; 22 (1): 64-77.e6

  Abstract

  Bone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions. Endosteal AML cells produce pro-inflammatory and anti-angiogenic cytokines and gradually degrade endosteal endothelium, stromal cells, and osteoblastic cells, whereas central marrow remains vascularized and splenic vascular niches expand. Remodeled endosteal regions have reduced capacity to support non-leukemic HSCs, correlating with loss of normal hematopoiesis. Preserving endosteal endothelium with the small molecule deferoxamine or a genetic approach rescues HSCs loss, promotes chemotherapeutic efficacy, and enhances survival. These findings suggest that preventing degradation of the endosteal vasculature may improve current paradigms for treating AML.

  View details for DOI 10.1016/j.stem.2017.11.006

  View details for PubMedID 29276143

  View details for PubMedCentralID PMC5766835